"We did these experiments thinking that we would show the importance of myofibroblasts and fibrosis in pancreas cancer progression, but the results went completely against that hypothesis," Kalluri said.
Since myofibroblasts and collagen are thought to block chemotherapy, the team treated their myofibroblast-depleted mice with gemcitabine, the standard treatment for pancreas cancer. The drug did not have any effect on the disease course or improve survival.
These results track those of a major clinical trial that combined a myofibroblast-depleting drug called a hedgehog inhibitor with gemcitabine to treat pancreatic cancer patients. The trial was stopped in 2012 when an interim analysis showed the patients taking the combination had faster disease progression than the control group that took only gemcitabine, a surprising result.
"This paradigm-shifting study identifies the reason why the hedgehog-inhibitor trials failed," said co-author Anirban Maitra, M.D., professor of Pathology and scientific director of the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research.
All solid tumors include some degree of fibrosis, Maitra said, but not as much as pancreas cancer.
The teams analysis of pancreatic tumors from 53 patients showed low levels of tumor myofibroblasts are associated with decreased survival.
Study findings are consistent with pathologic evidence that tumors with more fibrotic tissue more closely resemble normal pancreas tissue, indicating a better prognosis for patients, even though lab experiments indicated those tumors should be more aggressive, Maitra said.
"These findings also are likely to account for rather modest results in a phase I clinical trial of immunotherapy alone for pancreatic cancer," Maitra said.
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center